HER3/c-ErbB3 (referred to herein as ErbB3) is a member of the epidermal growth factor receptor (EGFR) family. ErbB3 binds neuregulin/heregulin (NRG/HRG). Receptors in the EGFR family are single transmembrane receptors with an intracellular tyrosine kinase domain. While the other EGFR family members (such as EGFR/HER1/ErbB1, HER2/ErbB2, and HER4/ErbB4) each have tyrosine kinase activity, ErbB3 has little or no tyrosine kinase activity, and thus is “kinase-dead.”
The extracellular domain (ECD) of the EGFR family contains four domains. Domains 1 and 3 (also known as domains L1 and L2) are responsible for ligand binding. Cysteine-rich domains 2 and 4 (also known as domains C1 and C2) are involved in dimerization with receptor partners. Upon ligand binding, the ECD undergoes conformational changes. The interaction of domains 2 and 4, which maintains the tethered (inactive) conformation of the receptor, is relieved, and an extended (active) conformation is adopted. The extended conformation favors dimerization with other receptor partners. HER2/ErbB2 is the only exception to this general rule, i.e., Her2-ECD is constitutively in the extended conformation.
Overexpression of ErbB3 is associated with poor prognosis in various carcinomas (e.g., breast, ovarian, prostate, colorectal, pancreatic, gastric, and head and neck cancers). Overexpression of ErbB3 also correlates with local to distal metastasis in lung, gastric, and colorectal cancers, and bone invasion in prostate cancer (Sithanandam et al., 2008, Cancer Gene Therapy 15:413). Overexpression of ErbB3 has been linked to resistance to several cancer treatments, including treatment with EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) and head and neck cancers, treatment with Her2 inhibitor in breast cancers, and treatment with radiotherapy in pancreatic cancers. Moreover, overexpression of NRG, a ligand for ErbB3, was also linked to resistance to EGFR tyrosine kinase inhibitor treatment. Chen et al. describe the use of anti-ErbB3 monoclonal antibodies that inhibit NRG function and show growth inhibitory activity against breast and ovarian cancer cells (Chen et al., 1996, J. Biol. Chem. 271: 7620).
ErbB3 has been found to be overexpressed in breast (Lemoine et al., Br. J. Cancer, 66:1116-1121 (1992)), gastrointestinal (Poller et al., J. Pathol., 168:275-280 (1992), Rajkumer et al., J. Pathol., 170:271-278 (1993), and Sanidas et al., Int. J. Cancer, 54:935-940 (1993)), and pancreatic cancers (Lemoine et at, J. Pathol., 168:269-273 (1992), and Friess et al., Clinical Cancer Research, 1:1413-1420 (1995)).
Therefore, there is a need in the art for an improved anti-ErbB3 antibodies that can be used as therapeutic agents.